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BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization

Abstract

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body1. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely2,3, is released on neuron depolarization1, and triggers rapid intracellular signals4 and action potentials in central neurons5. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens6,7,8 both during development and in adulthood. BDNF from corticostriatal neurons3 also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats9. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction10, schizophrenia11 or Parkinson's disease12, in which D3 receptor expression is abnormal.

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Figure 1: Dopamine D3 receptor and TrkB expressions in 6-OHDA-lesioned rats.
Figure 2: Impaired D3 receptor expression in developing BDNF-/-mice.
Figure 3: Levodopa-induced D3 receptor expression and behavioural sensitization in 6-OHDA-lesioned rats require BDNF and participation of the frontal cortex.
Figure 4: Levodopa upregulates BDNF expression in frontal cortex of 6-OHDA-lesioned rats.
Figure 5: Levodopa treatments upregulate TrkB receptor expression in striatum of 6-OHDA-lesioned rats.

References

  1. Thoenen, H. Neurotrophins and neuronal plasticity. Science 270, 593–598 (1995).

    Article  CAS  ADS  Google Scholar 

  2. von Bartheld, C. S., Byers, M. R., Williams, R. & Bothwell, M. Anterograde transport of neurotrophins and axodendritic transfer in the developing visual system. Nature 379, 830–833 (1996).

    Article  CAS  ADS  Google Scholar 

  3. Altar, C. A. et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389, 856–860 (1997).

    Article  CAS  ADS  Google Scholar 

  4. Altar, C. A. & DiStefano, P. S. Neurotrophin trafficking by anterograde transport. Trends Neurosci. 21, 433–437 (1998).

    Article  CAS  Google Scholar 

  5. Kafitz, K. W., Rose, C. R., Thoenen, H. & Konnerth, A. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 401, 918–921 (1999).

    Article  CAS  ADS  Google Scholar 

  6. Sokoloff, P., Giros, B., Martres, M.-P., Bouthenet, M.-L. & Schwartz, J.-C. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347, 146–151 (1990).

    Article  CAS  ADS  Google Scholar 

  7. Diaz, J. et al. Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain. J. Neurosci. 17, 4282–4292 (1997).

    Article  CAS  Google Scholar 

  8. Pilla, M. et al. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature 400, 371–375 (1999).

    Article  CAS  ADS  Google Scholar 

  9. Bordet, R. et al. Induction of dopamine D3 receptor as a mechanism of behavioral sensitization to levodopa. Proc. Natl Acad. Sci. USA 94, 3363–3367 (1997).

    Article  CAS  ADS  Google Scholar 

  10. Staley, J. K. & Mash, D. C. Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J. Neurosci. 16, 6100–6106 (1996).

    Article  CAS  Google Scholar 

  11. Gurevich, E. V. et al. Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. Arch. Gen. Psychiatry 54, 225–232 (1997).

    Article  CAS  Google Scholar 

  12. Ryoo, H. L., Pierrotti, D. & Joyce, J. N. Dopamine D3 receptor is decreased and D2 receptor is elevated in the striatum of Parkinson's disease. Mov. Disord. 13, 788–797 (1998).

    Article  CAS  Google Scholar 

  13. Lévesque, D. et al. A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons. Proc. Natl Acad. Sci. USA 92, 1719–1723 (1995).

    Article  ADS  Google Scholar 

  14. Seroogy, K. B. et al. Dopaminergic neurons in rat ventral midbrain express Brain-Derived Neurotrophic Factor and Neurotrophin-3 mRNAs. J. Comp. Neurol. 342, 321–334 (1994).

    Article  CAS  Google Scholar 

  15. Conner, J. & Lauter, J. C. Distribution of Brain-Derived Neurotrophic Factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17, 2295–2313 (1997).

    Article  CAS  Google Scholar 

  16. Numan, S. & Seroogy, K. B. Increased expression of TrkB mRNA in rat caudate-putamen following 6-OHDA lesions of the nigrostriatal pathway. Eur. J. Neurosci. 9, 489–495 (1997).

    Article  CAS  Google Scholar 

  17. Korte, M. et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl Acad. Sci. USA 92, 8856–8860 (1995).

    Article  CAS  ADS  Google Scholar 

  18. Ernfors, P., Lee, K.-F. & Jaenisch, R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150 (1994).

    Article  CAS  ADS  Google Scholar 

  19. Cabelli, R. J., Shelton, D. L., Segal, R. A. & Shatz, C. J. Blockade of endogenous ligands of TrkB inhibits formation of ocular dominance columns. Neuron 19, 63–76 (1997).

    Article  CAS  Google Scholar 

  20. Berendse, H. W., Galis-de-Graaf, Y. & Groenewegen, H. J. Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J. Comp. Neurol. 316, 314–347 (1992).

    Article  CAS  Google Scholar 

  21. Huang, Q. et al. Immunohistochemical localization of the D1 dopamine receptor in rat brain reveals its axonal transport, pre- and post-synaptic localization, and prevalence in the basal ganglia, limbic system and thalamic reticular nucleus. Proc. Natl Acad. Sci. USA 89, 11988–11992 (1992).

    Article  CAS  ADS  Google Scholar 

  22. Cole, D. G., Kobierski, L. A., Konradi, C. & Hyman, S. E. 6-hydroxydopamine lesions of the rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons. Proc. Natl Acad. Sci. USA 91, 9631–9635 (1994).

    Article  CAS  ADS  Google Scholar 

  23. Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J. & Greenberg, M. E. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709–726 (1998).

    Article  CAS  Google Scholar 

  24. Shieh, P. B., Hu, S. C., Bobb, K., Timmusk, T. & Ghosh, A. Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20, 727–740 (1998).

    Article  CAS  Google Scholar 

  25. Flores, G., Barbeau, D., Quirion, R. & Srivastava, L. K. Decreased binding of dopamine D3 receptors in limbic subregions after neonatal bilateral lesion of rat hippocampus. J. Neurosci. 16, 2020–2026 (1996).

    Article  CAS  Google Scholar 

  26. Whitelaw, R. B., Markou, A., Robbins, T. W. & Everitt, B. J. Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology 127, 213–224 (1996).

    Article  CAS  Google Scholar 

  27. O'Brien, C. P., Childress, A. R., McMellan, A. T. & Ehrman, R. A. A learning model of addiction. Res. Publ. Assoc. Res. Nervous Mental Dis. 70, 157–177 (1992).

    CAS  Google Scholar 

  28. Horger, B. A. et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J. Neurosci. 19, 4110–4122 (1999).

    Article  CAS  Google Scholar 

  29. Carlsson, A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1, 179–186 (1988).

    Article  CAS  Google Scholar 

  30. Diaz, J. et al. Phenotypical characterization of neurons expressing the dopamine D3 receptor. Neuroscience 65, 731–745 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank V. Mignon for technical assistance and C. Degott for providing the anti-IgG antibody. O.G. received grants from Fondation pour la Recherche Médicale and Lundbeck Foundation. This work was supported by grants from the European Commission (Fifth Framework Programme) and the National Institute on Drug Abuse to P.S.

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Guillin, O., Diaz, J., Carroll, P. et al. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411, 86–89 (2001). https://doi.org/10.1038/35075076

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